Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behavior. These phenomena have been linked with dopamine (DA) function within the ventral striatum and amygdala and have been described specifically in terms of incentive motivational processes. Our data show that persistent drug-induced enhancement in incentive motivation are associated with, and can be mimicked by, increases in limbic-striatal DA/cAMP/PKA/CREB activity, suggesting that adaptations in DA-regulated intracellular signaling molecules may underlie these behavioral changes. The current proposal will determine how PKA/CREB signaling within the amygdala contributes to associative aspects of incentive motivational processes by using Pavlovian-to-lnstrumental Transfer (PIT) and responding for Conditioned Reinforcement (CR) paradigms. This project will focus on the hypothesis that repeated cocaine exposure will result in persistent enhancements in incentive motivational processes due to alterations in the PKA/CREB signaling pathway in the amygdala. Specifically, we will investigate the following hypotheses. (1) Repeated cocaine exposure enhances incentive motivation and results in alterations of PKA/CREB FosB function in the amygdala. Behavioral and molecular alterations will be examined in rats previously-exposed to cocaine either responding in the presence of (PIT) or for (CR) food-paired conditioned stimuli. (2) Activation of PKA/CREB signaling in drug naive animals will augment incentive motivation. This will be examined using infusions of direct activators/inhibitors of PKA and viral vectors that over-express CREB or mutant CREB into the basolateral or central nucleus of the amygdala. (3) Inhibition of PKA/CREB signaling will block augmented incentive motivation in cocaine-treated animals. Correlations between behavior and CREB activity will also be examined in CRE-LacZ transgenic mice. Together these studies will determine whether cocaine-induced activation of the PKA/CREB signaling pathway in the amygdala results in augmented incentive motivation and whether these effects can be mimicked or blocked by manipulations that stimulate or inhibit PKA/CREB signaling, respectively. These data may be critical for understanding the neurobiology of motivational processes and their putative impact on drug-seeking behavior. Persistent alterations in PKA/CREB signaling in limbic-striatal regions produced by cocaine are hypothesized to contribute to compulsive reward seeking in addiction.